Group A streptococcal cell walls (SCW) induce a biphasic pattern of polyarthritis and hepatic granuloma formation in susceptible rats. We have continued to explore the cellular and molecular events leading to these chronic inflammatory lesions. TGF-beta, a potent immunomodulatory cytokine, is found synovium. Systemically administered TGF-beta suppresses the acute and chronic arthritis. In order to determine if TGF-beta contributes to the pathology in these lesions, we injected intraarticularly a monoclonal antibody to TGF-beta (1D11.16) or an irrelevant antibody (MOPC21) into rats at the time of the SCW intraperitoneal injection. Treatment of the rats with mAb 1D11.16 markedly reduced both the acute and chronic responses. The histopathology revealed a marked reduction in mononuclear infiltration, and cartilage and bone destruction. In additional studies, because of the effects of interleukin 4 (I1-4) on hematopoietic cells and its inhibitory effect on certain pro-inflammatory monokines, we evaluated the effect of daily systemic administration of murine recombinant IL-4 on the evolution of SCW-induced arthritis. IL-4 had little effect on the acute phase, but significantly suppressed the chronic phase, confirmed by histopathologic analysis. IL-4 inhibited O2 production both in vivo and in vitro. Additional studies examined the role of Kupffer cells in SCW-induced hepatic granuloma formation. These studies focus on the network of cell-cell interactions and cytokines involved in regulating chronic, inflammatory processes.